P1231: ZILOVERTAMAB VEDOTIN (MK-2140) FOR THE TREATMENT OF NON-HODGKIN LYMPHOMA: THE PHASE 1 DOSE ESCALATION AND COHORT EXPANSION WAVELINE-001 STUDY OF AN ANTI-ROR1 ANTIBODY-DRUG CONJUGATE
Authors: M. Wang, M. Mei, P. M. Barr, J. Barrientos, S. de Vos, R. Furman, K. Patel, P. A. Thompson, M. Choi, A. Kallam, Y. Zhu, S. Chakraborty, P. Marinello, S. E. Spurgeon
Journal: HemaSphere (2022)

Background: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein overexpressed in hematological malignancies. Zilovertamab vedotin (MK-2140) is an antibody-drug conjugate comprising a humanized IgG1 monoclonal antibody, a proteolytically cleavable linker, and the antimicrotubule cytotoxic agent monomethyl auristatin E (MMAE). The cytotoxicity of zilovertamab vedotin in hematologic cell lines has been demonstrated in preclinical studies. Aims: This first human phase 1 dose escalation study, WAVELINE-001 (NCT03833180), evaluated safety and efficacy of zilovertamab vedotin at various doses in patients (pts) with relapsed/refractory hematologic malignancies. Methods: Eligible pts aged ≥18 years with an ECOG PS of 0-2 and histological diagnosis of chronic lymphocytic leukemia/small lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, acute lymphoid leukemia, acute myeloid leukemia, or non-Hodgkin lymphoma (NHL; mantle cell lymphoma [MCL], follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma [DLBCL], Richter transformation, Burkitt lymphoma, and T-cell-NHL) were enrolled. Pts received zilovertamab vedotin intravenously at starting doses of 0.50 mg/kg (up to 2.5 mg/kg) on day 1 every 3 weeks (Q3W) (Schedule 1), 1.0 mg/kg (planned up to 2.25 mg/kg) on day 1 and 8 Q3W (Schedule 2), or 1.0 mg/kg (planned up to 2.25 mg/kg) on days 1, 8, and 15 Q4W (Schedule 3) using an accelerated plus 3 + 3 dose-escalation design. Primary end point was determination of the maximum tolerated dose (MTD). Secondary end points included safety, objective response rate (ORR), and duration of response (DOR). Data for pts with NHL enrolled in Schedule 1 are presented. Results: A total of 51 pts were enrolled in Schedule 1 (starting dose 0.5 [n=1], 1.00 [n=3], 1.50 [n=3], 2.00 [n=3], 2.25 [n=11], or 2.50 [n=30] mg/kg) as of the data cutoff of May 18, 2021. Median age was 70 (range, 44-91) years, 54.9% of pts were male, 49.0% had an ECOG PS of 0, and 41/51 (80%) were diagnosed with NHL; 13/51 (25.5%) were diagnosed with DLBCL and 17/51 (33.3%) were diagnosed with MCL. 15 pts (29.4%) received prior CAR-T/CAR-NK. Enrollment in Schedules 2 and 3 is currently ongoing. The MTD for Schedule 1 was determined to be 2.5 mg/kg. Treatment-related adverse events (AEs) occurred in 37 pts (72.5%), most commonly (≥20%) peripheral neuropathy (47.0%), fatigue (37.3%), neutrophil count decrease (31.4%), nausea (27.5%), and diarrhea (21.6%); 24 pts (47.1%) experienced a grade ≥3 treatment-related AE. One pt died due to acute respiratory failure; however, it was not considered treatment-related by the investigator. For Schedule 1, after a median (range) follow-up of 17.3 (range, 1.2-25.8) mo, ORR was 36.6% (15/41 [95% CI, 22.1%-53.1%]; 5 CR; 10 PR) among all pts with NHL. For pts in the NHL group who had DLBCL (n=13), ORR was 38.5% (95% CI, 13.9%-68.4%; CR 3; PR 2). For pts from the NHL group who had MCL (n=17), ORR was 52.9% (95% CI, 27.8%-77.0%; CR 2; PR 7). For pts with DLBCL and MCL, 9/13 (69.0%) and 9/17 (53%) had any decrease in target lesions, respectively. Median DOR was 7.8 mo (range, 2.1-17.6+ mo) among all pts in Schedule 1 with NHL who achieved a response; 4.6 mo (range, 2.9-17.6) for DLBCL and 10 mo (range, 2.1-15.7) for MCL. For pts who received prior CAR-T/CAR-NK, the ORR was 40.0% (95% CI, 16.3%-67.6%); 2 pts had a CR and 4 had a PR. Summary/Conclusion: Targeting the ROR1 pathway with zilovertamab vedotin is associated with a tolerable safety profile and promising antitumor activity in pts with relapsed/refractory NHL.